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OBJECTIVE: T lymphocytes play an important role in systemic sclerosis (SSc), a connective tissue disease characterized by inflammation, fibrosis, and vascular damage. While their precise role and antigen specificity are unclear, T cell-derived cytokines likely contribute to the induction of fibrosis. The aim of this study was to establish the role of cytokine dysregulation by T cells in the pathogenesis of SSc. METHODS: To identify relationships between a specific cytokine, T cell subset, and the disease course, we studied a large cohort of patients with diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc). Using Luminex analysis and intracellular cytokine staining, we analyzed the intrinsic ability of CD4+ and CD8+ T cell subsets to produce cytokines following in vitro activation. RESULTS: High levels of the profibrotic type 2 cytokine interleukin-13 (IL-13) were produced following activation of peripheral blood effector CD8+ T cells from SSc patients as compared with normal controls or with patients with rheumatoid arthritis. In contrast, CD4+ T cells showed a lower and more variable level of IL-13 production. This abnormality correlated with the extent of fibrosis and was more pronounced in dcSSc patients than in lcSSc patients. CONCLUSION: Dysregulated IL-13 production by effector CD8+ T cells is important in the pathogenesis of SSc and is critical in the predisposition to more severe forms of cutaneous disease. Our study is the first to identify a specific T cell phenotype that correlates with disease severity in SSc and can be used as a marker of immune dysfunction in SSc and as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

OBJECTIVE: A phase II randomized controlled trial of recombinant human relaxin suggested that a dosage of 25 mug/kg/day was safe and clinically effective in improving skin disease and reducing functional disability in scleroderma (systemic sclerosis; SSc). We undertook a large randomized, double-blind, placebo-controlled clinical trial to compare placebo with 10 mug/kg/day and 25 mug/kg/day recombinant human relaxin, given for 24 weeks in patients with stable, diffuse, moderate-to-severe SSc. METHODS: Men and women ages 18-70 years with diffuse cutaneous SSc (dcSSc) were administered recombinant human relaxin (10 mug/kg/day or 25 mug/kg/day) or placebo for 24 weeks as a continuous subcutaneous infusion. There was a followup safety visit at week 28. RESULTS: The primary outcome measure, the modified Rodnan skin thickness score, was similar among the 3 groups at baseline and at weeks 4, 12, and 24. Secondary outcomes such as functional disability were similar in all 3 groups, while the forced vital capacity decreased significantly in the relaxin groups. The discontinuation of both doses of relaxin at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as doubling of serum creatinine, renal crisis, or grade 3 or 4 essential hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo. CONCLUSION: Recombinant relaxin was not significantly better than placebo in improving the total skin score or pulmonary function or in reducing functional disability in patients with dcSSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To describe the classification, demographic and clinical features, and survival in anti-U3 RNP autoantibody-positive patients with systemic sclerosis (SSc). METHODS: Medical records of 108 anti-U3 RNP-positive and 2,471 anti-U3 RNP-negative SSc patients first evaluated during 1985-2003 were reviewed. Anti-U3 RNP antibody was detected by protein and RNA immunoprecipitation. Disease classification, demographic and clinical features, organ system involvement, and survival were compared between the 2 patient groups, by Student's t-test, chi-square analysis, and Mantel-Haenszel test. RESULTS: The anti-U3 RNP-positive group had a higher proportion of African American patients (27% versus 5%; P < 0.001) and male patients (29% versus 19%; P = 0.021), and was younger at the time of first physician diagnosis (mean age 42.8 years versus 47.4 years; P = 0.001). The 2 groups had similar proportions of patients with diffuse cutaneous involvement (47% and 45% in those with and those without anti-U3 RNP, respectively). However, among patients with diffuse cutaneous involvement, the mean maximum modified Rodnan skin score was significantly lower in the anti-U3 RNP group (22.3 versus 27.9; P < 0.001). Skeletal muscle involvement was more frequent in anti-U3 RNP-positive patients (25% versus 14%; P = 0.002), as was 'intrinsic' pulmonary arterial hypertension (PAH) (31% versus 13%; P < 0.001). The frequency of gastrointestinal involvement, cardiac involvement, pulmonary fibrosis, and 'renal crisis' did not differ significantly between the 2 groups. Survival was worse in the anti-U3 RNP-positive group (hazard ratio 1.38 [95% confidence interval 1.05-1.82]). PAH was the most common known cause of death in patients with anti-U3 RNP (30%, versus 10% in the anti-U3 RNP-negative group; P < 0.001). CONCLUSION: The present findings demonstrate that the frequencies of African American race and male sex are greater among SSc patients with anti-U3 RNP antibody than those without, and the former group is younger at SSc diagnosis. Anti-U3 RNP-positive patients have more frequent skeletal muscle involvement and PAH, the latter being the most common cause of death. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We have recently developed an enzyme-linked immunosorbent assay (ELISA) for detection of anti-RNA polymerase III (anti-RNAP III) antibody, using a recombinant fragment containing the immunodominant epitope as the antigen source. This study was conducted to assess the analytical accuracy and clinical associations of the anti-RNAP III ELISA in patients with systemic sclerosis (SSc). METHODS: To evaluate analytical sensitivity and specificity of the ELISA, both immunoprecipitation tests and ELISA were used to detect anti-RNAP III antibody in 534 SSc sera from patients at 3 medical centers. Sera from 522 SSc patients and 516 controls, including patients with other connective tissue diseases and blood bank donors, were also evaluated to assess the clinical sensitivity and specificity of the ELISA. Clinical findings in anti-RNAP III antibody-positive SSc patients were compared between patient groups stratified according to anti-RNAP III antibody levels determined by the ELISA. RESULTS: In SSc patients, our ELISA showed analytical sensitivity of 91% and analytical specificity of 99% compared with the immunoprecipitation assay (a gold standard for detection of anti-RNAP III antibody). The additional analysis using a large series of SSc and control sera showed that clinical sensitivity and specificity of the ELISA with respect to the diagnosis of SSc were 17% and 98%, respectively. A high level of anti-RNAP III antibody was associated with diffuse cutaneous SSc, higher maximum total skin score, and increased frequency of tendon friction rubs. CONCLUSION: The anti-RNAP III ELISA is analytically accurate and clinically specific. With this assay, testing for anti-RNAP III antibody can be made routinely available. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to describe clinical manifestations in patients with Th/To antibody-positive systemic sclerosis (SSc) during long-term follow-up., Methods: We performed a case-control study involving anti-Th/To antibody-positive patients with SSc who were newly referred to the University of Pittsburgh Medical Center and the Pittsburgh Scleroderma Center from 1980 to 2015. For every case, 2 anti-Th/To antibody-negative SSc patients (the first 2 consecutively seen after a case) were used as controls. Long-term disease manifestations and survival were then compared between cases and controls., Results: A total of 204 anti-Th/To antibody-positive SSc patients and 408 controls were identified. The cohort had a mean ± SD age of 52 ± 12.9 years, and 76% of individuals were women. Anti-Th/To antibody-positive patients more often presented without skin thickening (P < 0.0001) and had a higher rate of pulmonary hypertension (PH) (P < 0.0001) and interstitial lung disease (P = 0.05) compared to anti-Th/To antibody-negative SSc controls. Anti-Th/To antibody-positive SSc patients also had less frequent muscle and joint involvement than anti-Th/To antibody-negative SSc controls (P < 0.0001). After a median clinical follow-up period of 6.1 years (interquartile range 2.4-12.7), 38% of anti-Th/To-positive patients had developed PH compared to 15% of anti-Th/To antibody-negative SSc controls (P < 0.0001). The rate of PH classified as World Health Organization (WHO) Group 1 pulmonary arterial hypertension [PAH] was 23% in anti-Th/To-positive patients compared to 9% in anti-Th/To antibody-negative SSc controls (P < 0.0001). After adjusting for age and sex, anti-Th/To antibody positivity was associated with a hazard ratio (HR) of 3.3 (95% confidence interval 2.3-4.9) for increased risk of developing PH at 10 years of follow-up from the first scleroderma center visit., Conclusion: This is the largest cohort of patients with anti-Th/To antibody-positive SSc with long-term follow-up data. The very high rate (38%) and associated independent risk of anti-Th/To antibody-positive patients developing PH in follow-up, particularly in WHO Group 1 PAH patients, is striking. Patients presenting with limited skin involvement should be tested for Th/To antibodies, and if present, careful monitoring for PH is warranted., (© 2022 American College of Rheumatology.)

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1 * 08:04 and HLA-DRB1 * 11:02 alleles were associated with overall SSc risk, and the HLA-DRB1 * 08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1 * 13:01 and HLA-DRB1 * 07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1 * 13:01 allele with the ATA + subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1 * 13:01 allele frequency in multiple populations was observed ( r = 0.98, P = 3 × 10 -6 ). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc., Competing Interests: Competing interest statement: M.D.M. received consulting fees from Mitsubishi Tanabe, Astellas, Boehringer Ingelheim, Gerson Lehrman Group, Smart Analyst, and Guidepoint Global. R.T.D. received consulting fees from Eicos Sciences. D.K. received consulting fees from Actelion, Bristol-Myers Squibb, CSL Behring, Inventiva, EMD Merck-Serono, Sanofi-Aventis, GlaxoSmithKline, Corbus, Cytori, UCB, Bayer, Boehringer Ingelheim, and Genentech-Roche, and research support from Bayer, Bristol-Myers Squibb, and Pfizer, and owns stock or stock options in Eicos Sciences, Inc. (CiViBioPharma, Inc.). L.A.S. received consulting fees from Axon Pharma. H.G. received consulting fees from Pfizer, AbbVie, Actelion, and Horizon Pharmaceuticals. C.T.D. received research support from Gilead, Actelion, and Cytori. V.K.S. received research support from AbbVie. E.J.B. received consulting fees from Genentech. L.C. received consulting fees or served on the board of Reata, Bristol-Myers Squibb, Boehringer-Ingelheim, Eicos, and Mitsubishi Tanabe. S.L.B. and M.J.D. are coauthors on a 2015 research article., (Copyright © 2020 the Author(s). Published by PNAS.)

The pathology of skin involvement in systemic sclerosis (or scleroderma) was first described in detail in 1892. In this article, we trace the history of cutaneous scleroderma and the evolution of thinking of scholars who have addressed this topic. We focus on skin histopathologic abnormalities and both clinical and laboratory techniques proposed for quantifying skin thickening and mobility. We examine the development of the simple bedside physical examination method of Dr Gerald Rodnan, first published in the 1970s and subsequently modified by others in the early 1990s (modified Rodnan skin score). This method has been found to be the only completely validated technique for assessing skin thickness in systemic sclerosis. Now nearly 50 years later, the modified Rodnan skin thickness scoring system remains the gold standard for use in both systemic sclerosis clinical trials and observational studies., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Background: Systemic sclerosis (SSc) is a rare autoimmune fibrosing disease with an incompletely understood genetic and non-genetic etiology. Defining its etiology is important to allow the development of effective predictive, preventative, and therapeutic strategies. We conducted this epigenomic study to investigate the contributions of DNA methylation to the etiology of SSc while minimizing confounding due to genetic heterogeneity., Methods: Genomic methylation in whole blood from 27 twin pairs discordant for SSc was assayed over 450 K CpG sites. In silico integration with reported differentially methylated cytosines, differentially expressed genes, and regulatory annotation was conducted to validate and interpret the results., Results: A total of 153 unique cytosines in limited cutaneous SSc (lcSSc) and 266 distinct sites in diffuse cutaneous SSc (dcSSc) showed suggestive differential methylation levels in affected twins. Integration with available data revealed 76 CpGs that were also differentially methylated in blood cells from lupus patients, suggesting their role as potential epigenetic blood biomarkers of autoimmunity. It also revealed 27 genes with concomitant differential expression in blood from SSc patients, including IFI44L and RSAD2. Regulatory annotation revealed that dcSSc-associated CpGs (but not lcSSc) are enriched at Encyclopedia of DNA Elements-, Roadmap-, and BLUEPRINT-derived regulatory regions, supporting their potential role in disease presentation. Notably, the predominant enrichment of regulatory regions in monocytes and macrophages is consistent with the role of these cells in fibrosis, suggesting that the observed cellular dysregulation might be, at least partly, due to altered epigenetic mechanisms of these cells in dcSSc., Conclusions: These data implicate epigenetic changes in the pathogenesis of SSc and suggest functional mechanisms in SSc etiology.

Background: Systemic sclerosis (SSc) is a female-predominant disease, characterized by excessive extracellular matrix deposition (ECM) with dermal and internal organ fibrosis. Considering the sex-based disparity in disease incidence, estradiol (E2), an estrogen form with pro-fibrotic effects, may play a role in SSc. We reported that post-menopausal women with diffuse cutaneous (dc)SSc have higher serum E2 levels compared to similar aged, healthy controls. Since males with SSc tend to have more severe disease, we examined serum E2 in dcSSc males in relation to disease characteristics and survival., Methods: We measured serum E2 in 83 dcSSc men > 50 years old from the University of Pittsburgh Scleroderma Center and similar aged healthy controls. Using statistical modeling, we examined the associations between serum E2, internal organ involvement, autoantibody profiles, and survival., Results: Male dcSSc patients had significantly higher serum E2 levels compared to healthy males and similar aged dcSSc post-menopausal women. Male dcSSc patients with high serum E2 had significantly more heart involvement, a trend for higher skin thickness progression rate, and worse survival. Using Cox regression modeling, increased serum E2 levels in anti-Scl-70 antibody-positive dcSSc males were associated with an increased risk of death., Conclusions: dcSSc males > 50 years old have higher levels of serum E2 compared to healthy controls and dcSSc post-menopausal women. Elevated serum E2 levels in dcSSc males are associated with heart involvement, trend to progression of dermal fibrosis, and, if anti-Scl-70 antibody positive, worse survival. Our study expands on previous work implicating E2 in dermal fibrosis in SSc and associates E2 levels with internal organ involvement and survival. These data suggest a role for estrogen imbalance in dcSSc.

Objective: Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients., Methods: SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls., Results: Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 × 10 -4 )., Conclusion: In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility., (© 2018, American College of Rheumatology.)

Background: IL-13-producing CD8 + T cells have been implicated in the pathogenesis of type 2-driven inflammatory human conditions. We have shown that CD8 + IL-13 + cells play a critical role in cutaneous fibrosis, the most characteristic feature of systemic sclerosis (SSc; scleroderma). However, the molecular mechanisms underlying production of IL-13 and other type 2 cytokines by CD8 + T cells remain unclear., Objective: We sought to establish the molecular basis of IL-13 overproduction by CD8 + T cells from patients with SSc, focusing on T-bet modulation of GATA-3 activity, which we showed to underlie IL-13 overproduction in CD8 + IL-13 + cells from patients with SSc., Methods: Biochemical and biophysical methods were used to determine the expression and association of T-bet, GATA-3, and regulatory factors in CD8 + T cells isolated from the blood and lesional skin of patients with SSc with severe skin thickening. Chromatin immunoprecipitation analysis determined GATA-3 binding to the IL-13 promoter. ImageStream analysis and confocal microscopy visualized the subcellular localization of T-bet and GATA-3. Transcript levels were decreased by small interfering RNAs., Results: Interaction of T-bet with the adaptor protein 14-3-3z in the cytosol of CD8 + T cells from patients with SSc reduces T-bet translocation into the nucleus and its ability to associate with GATA-3, allowing more GATA-3 to bind to the IL-13 promoter and inducing IL-13 upregulation. Strikingly, we show that this mechanism is also found during type 2 polarization of CD8 +  T cells (T C 2) from healthy donors., Conclusions: We identified a novel molecular mechanism underlying type 2 cytokine production by CD8 + T cells, revealing a more complete picture of the complex pathway leading to SSc disease pathogenesis., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets., Methods: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed., Results: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly)., Conclusions: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).

Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 ± 13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ≤50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Loss of CD28 expression by CD8 + T cells occurs with age and during chronic inflammatory conditions. CD8 + CD28 - T cells are a heterogeneous cell subpopulation whose function ranges from immunosuppressive to effector. Here we analyzed the role of CD8 + CD28 - T cells in the pathogenesis of systemic sclerosis (SSc), a connective tissue disorder characterized by autoimmunity, vasculopathy, and extensive cutaneous and visceral fibrosis. We show that the frequency of CD8 + CD28 - T cells is increased in the blood and affected skin of SSc patients, independent of patient age, and correlates with the extent of skin fibrosis. We found that most skin-tropic CD8 + CD28 - T cells are resident in the skin lesions of patients in the early stage of the disease, exhibit an effector memory phenotype, and present a strong cytolytic activity ex vivo. Skin-resident and circulating SSc CD8 + CD28 - T cells produce high levels of the profibrotic cytokine IL-13, which induces collagen production by normal and SSc dermal fibroblasts. Thus, our findings indicate that CD8 + CD28 - T cells represent a pathogenic T-cell subset in SSc and likely play a critical role in the early stage of SSc skin disease., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: We sought to identify the clinical factors associated with calcinosis in an international multicenter collaborative effort with the Scleroderma Clinical Trials Consortium (SCTC)., Methods: This is a retrospective cohort study of 5218 patients with systemic sclerosis (SSc). Logistic regression was used to obtain odds ratios (OR) relating calcinosis to various clinical features in multivariate analyses., Results: A total of 1290 patients (24.7%) had calcinosis. In univariate analyses, patients with calcinosis were older than patients without calcinosis, more likely to be female, and had longer disease duration from the first non-Raynaud phenomenon symptom. Patients with calcinosis were more likely to have digital ulcers, telangiectasias, acro-osteolysis, cardiac disease, pulmonary hypertension, gastrointestinal involvement, arthritis, and osteoporosis, but less likely to have muscle disease. Anti-Scl-70, RNA-polymerase-III, and U1-RNP autoantibodies were significantly less common in patients with calcinosis, while anticentromere (ACA), anti-PM/Scl, and anticardiolipin antibodies were more frequent. In multivariate analysis, the strongest associations with calcinosis were digital ulcers (OR = 3.9; 95% CI: 2.7-5.5; p < 0.0001) and osteoporosis (OR = 4.2; 95% CI: 2.3-7.9; p < 0.0001)., Conclusion: One quarter of patients with SSc have calcinosis at some time during their illness. Our data confirm a strong association of calcinosis with digital ulcers, and support a novel association with osteoporosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: There is a strong female preponderance reported in many connective tissue diseases and in almost all systemic sclerosis (SSc) case series., Methods: We compared gender differences in SSc patients in a large single-center cohort, including demographic features, disease subtype, environmental exposures, disease-specific serum autoantibodies, organ system involvement (frequency and severity) and survival. Adjustment for cutaneous subset (diffuse cutaneous [dc] and limited cutaneous [lc]) was performed., Results: We identified key characteristics which distinguished female from male SSc patients. Females were more frequently younger at disease onset with a longer disease duration at the time of their first visit. Females more often had lcSSc and, if an overlap syndrome was present, it was most often systemic lupus erythematosus. In contrast, males more frequently had dcSSc and overlap with myositis. Females more frequently had peripheral vascular involvement but in males it was more often severe. Males were more often cigarette smokers and more frequently had environmental exposures. Males more frequently had interstitial lung disease (ILD or pulmonary fibrosis) which was more severe. Females had a significantly increased frequency of anti-centromere antibody and males anti-topoisomerase I and anti-U3RNP antibody. Males had significantly reduced survival (73% at 5 years and 45% at 10 years after onset of SSc). The most frequent causes of death were ILD in males and pulmonary hypertension in females., Conclusions: Gender differences may be important clues to understanding the natural history and pathogenesis of SSc., Competing Interests: Disclosures Conflict of interest: None of the authors has financial interest related to this study to disclose.

Objective: Although diffuse cutaneous systemic sclerosis (dcSSc) is associated with a reduction in life expectancy, there are no validated prognostic models for determining 5-year mortality in patients with dcSSc. The objective of this study was to derive and validate a rule for predicting 5-year mortality in patients with early dcSSc., Methods: We studied an inception cohort of 388 US Caucasian patients with early dcSSc (<2 years from the appearance of the first symptom). Predefined baseline variables were analyzed in a stepwise logistic regression model in order to identify factors independently associated with 5-year all-cause mortality. We rounded the beta weights to the nearest integer and summed the points assigned to each variable in order to stratify patients into low-risk (<0 points), moderate-risk (1-2 points), and high-risk (≥3 points) groups. We then applied this rule to an external validation cohort of 144 Caucasian patients with early dcSSc from the Royal Free Hospital cohort and compared stratum-specific 5-year mortality., Results: Six independent predictors (rounded beta weight) comprised the model: age at first visit (points allotted: -1, 0, or 1), male sex (points allotted: 0 or 1), tendon friction rubs (points allotted: 0 or 1), gastrointestinal involvement (points allotted: 0 or 1), RNA polymerase III antibodies (points allotted: 0 or 1), and anemia (points allotted: 0 or 1). The 3-level risk stratification model performed well, with no significant differences between the US derivation cohort and the UK validation cohort., Conclusion: We derived and externally validated, in US and UK cohorts, an easy-to-use 6-variable prediction rule that assigns low-risk, moderate-risk, and high-risk categories for 5-year mortality in patients with early dcSSc. Only history, physical examination, and basic laboratory assessments are required., (© 2016, American College of Rheumatology.)

Objectives: To evaluate endothelial function and vascular stiffness in large, medium, small and microcirculatory blood vessels in very early diffuse systemic sclerosis (SSc)., Methods: We studied consecutive early diffuse SSc patients, defined as <2 years from first SSc symptom who did not have a prior cardiovascular event. Age, gender and race-matched controls were recruited. All underwent assessment of aortic pulse wave velocity (PWV), carotid intima-media thickness (IMT) brachial flow-mediated dilation (FMD), digital peripheral artery tonometer (EndoPAT) assessment and laser speckle contrast imaging (LSCI)., Results: Fifteen early diffuse SSc and controls were evaluated. The average age was 49 years, 63% were female and 93% were Caucasian. There were no differences in body mass index, hypertension, diabetes or hyperlipidaemia between controls and SSc patients. Mean SSc disease duration was 1.3 years. In the large central vessels, there was no difference in aortic PWV (p=0.71) or carotid IMT (p=0.92) between SSc patients and controls. Similarly, there was no difference in endothelial dysfunction with brachial artery FMD after ischaemia (p=0.55) and nitroglycerin administration (p=0.74). There were significantly lower values for digital EndoPAT measures (p=0.0001) in SSc patients. LSCI revealed a distinct pattern of microcirculatory abnormalities in response to ischaemia in SSc patients compared to controls. Imaging demonstrated a blunted microcirculatory hyperaemia of the hand with greater subsequent response to nitroglycerin., Conclusions: These findings suggest that the earliest endothelial changes occur in smaller arterioles and microvascular beds, but not in medium or macrovascular beds, in early diffuse SSc.

Objectives: Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to develop an instrument for collating case data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement among experts on the probability that cases were classified as SSc., Study Design and Setting: A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and reranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICCs)., Results: Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14-22), fingertip lesions (9-21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7), and puffy fingers (5). The ICC across experts was 0.73 [95% confidence interval (CI): 0.58, 0.86] and improved to 0.80 (95% CI: 0.68, 0.90)., Conclusions: Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (range, 23-14) and weighted. Our methods reflect the rigors of measurement science and serve as a template for developing classification criteria., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Systemic sclerosis (SSc) is associated with a reduction in life expectancy, but there are no validated prognostic models for determining short-term mortality. The objective of this study was to derive and validate a prediction rule for 2-year mortality in patients with early diffuse cutaneous SSc (dcSSc)., Methods: We studied a prospectively enrolled cohort of 387 US Caucasian patients with early dcSSc (<2 years from the appearance of the first symptom), randomly divided into a derivation cohort (n = 260) and a validation cohort (n = 127). Predefined baseline predictor variables were analyzed in a stepwise multivariable logistic regression model in order to identify factors independently associated with 2-year all-cause mortality using a cutoff of P < 0.05. We rounded the beta values to the nearest integer and summed the points assigned to each variable in order to stratify patients into low-risk, moderate-risk, and high-risk groups. We then applied this rule to an external validation cohort of 110 Caucasian patients with early dcSSc from a single UK center and compared stratum-specific mortality using chi-square statistics., Results: Four independent predictor variables (with assigned integer values) comprised the model: age at first visit (points allotted: -1, 0, or 1), skin thickness progression rate (points allotted: 0 or 1), gastrointestinal tract severity (points allotted: 0, 1, or 2), and anemia (points allotted: 0 or 2). The prediction model performed well, with no significant differences between the derivation cohort and the US or UK validation cohorts in the low-risk and moderate-risk groups., Conclusion: We derived a 4-variable prediction rule that can be used to stratify patients with early dcSSc into groups by risk of 2-year mortality, and we validated that prediction rule in US and UK cohorts., (Copyright © 2014 by the American College of Rheumatology.)

Objective: To identify and characterize a novel systemic sclerosis (SSc)-related autoantibody directed against a complex consisting of RuvBL1 and RuvBL2 (RuvBL1/2) and to assess its clinical correlations., Methods: We first analyzed 316 consecutive patients with SSc who were evaluated at Kanazawa University Hospital. Controls included 290 patients with other connective tissue diseases, interstitial lung disease alone, or autoimmune hepatitis, and 50 healthy subjects. Autoantibody specificities were analyzed using RNA and protein immunoprecipitation assays. Autoimmune targets were affinity purified using patients' sera and subjected to liquid chromatography mass spectrometry. SSc patients in another institution in Japan and the University of Pittsburgh cohort were also included in analysis for evaluating clinical correlations., Results: By protein immunoprecipitation assay, 6 SSc sera (1.9%) reacted with doublets with molecular weights of ∼50 kd. Liquid chromatography mass spectrometry of the partially purified autoantigen and additional immunoblot-based analyses revealed that this antibody specificity recognized RuvBL1/2. Anti-RuvBL1/2 antibody was exclusively detected in SSc patients. SSc patients with anti-RuvBL1/2 in both the Japanese and Pittsburgh cohorts consistently had higher frequencies of SSc in overlap with myositis and diffuse skin thickening than those without anti-RuvBL1/2. Compared with other autoantibodies related to SSc/myositis overlap (anti-PM-Scl and anti-Ku), anti-RuvBL1/2 was distinctive in terms of its associations with older age at SSc onset, male sex, and a high frequency of diffuse cutaneous involvement., Conclusion: Anti-RuvBL1/2 antibody is a novel SSc-related autoantibody associated with a unique combination of clinical features, including myositis overlap and diffuse cutaneous involvement., (Copyright © 2014 by the American College of Rheumatology.)

Objective: To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) who had undergone routine screening for PAH at SSc centers in the US., Methods: The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma registry is a prospective registry of SSc patients at high risk for PAH or with definite pulmonary hypertension diagnosed by right-sided heart catheterization within 6 months of enrollment. Only patients with World Health Organization group I PAH (mean pulmonary artery pressure >25 mm Hg and pulmonary capillary wedge pressure <15 mm Hg without significant interstitial lung disease) were included in these analyses., Results: In total, 131 SSc patients with incident PAH were followed for a mean ± SD of 2.0 ± 1.4 years. The 1-, 2-, and 3-year cumulative survival rates were 93%, 88%, and 75%, respectively. On multivariate analysis, age >60 years (hazard ratio [HR] 3.0, 95% confidence interval [95% CI] 1.1- 8.4), male sex (HR 3.9, 95% CI 1.1-13.9), functional class (FC) IV status (HR 6.5, 95% CI 1.8 -22.8), and diffusing capacity for carbon monoxide (DLCO) <39% predicted (HR 4.2, 95% CI 1.3-13.8) were significant predictors of mortality., Conclusion: This is the largest study describing survival in patients with incident SSc-associated PAH followed up at multiple SSc centers in the US who had undergone routine screening for PAH. The survival rates were better than those reported in other recently described SSc-associated PAH cohorts. Severely reduced DLCO and FC IV status at the time of PAH diagnosis portended a poor prognosis in these patients.

Objective: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc., Methods: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc., Results: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc., Conclusions: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

Objective: Palpable tendon friction rubs (TFRs) in systemic sclerosis (SSc; scleroderma) have been associated with diffuse skin thickening, increased disability, and poor survival. Our objective was to quantify the prognostic implications of palpable TFRs on the development of disease complications and longer-term mortality in an incident cohort of early diffuse cutaneous SSc (dcSSc) patients., Methods: We identified early dcSSc patients (disease duration <2 years from the first SSc symptom) first evaluated at the University of Pittsburgh Scleroderma Center between 1980 and 2006 and found to have palpable TFRs. These patients were matched 1:1 with the next consecutive early dcSSc patient without TFRs as a control. All had ≥2 clinic visits and 5 years of followup from the first visit., Results: A total of 287 early dcSSc patients with TFR were identified and matched to 287 controls. The median disease duration was 0.83 years in TFR patients and 1.04 years in controls. The median followup was 10.1 years in TFR patients and 7.9 years in controls. Over the course of their illness, patients with TFRs had a >2-fold risk of developing renal crisis and cardiac and gastrointestinal disease complications, even after adjustment for other known risk factors. Patients with TFRs had poorer 5- and 10-year survival rates., Conclusion: Patients with early dcSSc having ≥1 TFRs are at an increased risk of developing renal, cardiac, and gastrointestinal involvement before and after their first Scleroderma Center visit and have reduced survival. Patients presenting with TFRs should be carefully monitored for serious internal organ involvement., (Copyright © 2013 by the American College of Rheumatology.)

Introduction: Systemic sclerosis (SSc) is more prevalent in women. Our goal is to determine the effects of 17β-estradiol (E2) on the development of fibrosis and to compare circulating levels of estrogens in SSc patients and healthy controls., Methods: Using primary human dermal fibroblasts, we evaluated the effect of E2 on fibronectin (FN) expression with and without the estrogen receptor (ER) antagonist ICI 182,780, inhibitors of signaling, propyl-pyrazole-triol, an ERα specific ligand, and genistein, an ERβ selective ligand, to identify the signaling pathways mediating E2's effect. We confirmed the fibrotic effect of E2 in human skin using an ex vivo organ culture model. Lastly, we measured levels of E2 and estrone in serum samples from SSc patients with diffuse cutaneous involvement and healthy controls using mass spectrometry., Results: E2 increased expression of FN in dermal fibroblasts. ICI 182,780, inositol-1,4,5-triphosphate inhibitor, and p38 mitogen-activated protein kinase inhibitor blocked the effects of E2 on FN. Propyl-pyrazole-triol, but not genistein, significantly increased FN expression. Ex vivo, E2 induced fibrosis of human skin. The effects of E2 were abrogated by ICI 182,780. Circulating levels of E2 and estrone were significantly increased in sera of patients with diffuse cutaneous SSc., Conclusion: Our findings implicate estrogens in the fibrotic process and may explain the preponderance of SSc in women. ICI 182,780 or other ER signaling antagonists may be effective agents for the treatment of fibrosis.

Objective: Fibrosis is a major contributor to morbidity and mortality in systemic sclerosis (SSc). T cells are the predominant inflammatory infiltrate in affected tissue and are thought to produce cytokines that drive the synthesis of extracellular matrix (ECM) proteins by fibroblasts, resulting in excessive fibrosis. We have previously shown that aberrant interleukin-13 (IL-13) production by peripheral blood effector CD8+ T cells from SSc patients correlates with the extent of skin fibrosis. The present study was undertaken to investigate the role of IL-13 production by CD8+ T cells in dermal fibrosis, an early and specific manifestation of SSc., Methods: ECM protein production by normal dermal fibroblasts cocultured with SSc CD8+ T cell supernatants was determined by quantitative polymerase chain reaction and Western blotting. Skin-homing receptor expression and IL-13 production by CD8+ T cells in the peripheral blood of SSc patients were measured by flow cytometry. IL-13+ and CD8+ cells in sclerotic skin were identified by immunohistochemistry., Results: IL-13-producing circulating CD8+ T cells from patients with SSc expressed skin-homing receptors and induced a profibrotic phenotype in normal dermal fibroblasts, which was inhibited by an anti-IL-13 antibody. High numbers of CD8+ T cells and IL-13+ cells were found in the skin lesions of SSc patients, particularly during the early inflammatory phase of the disease., Conclusion: These findings show that IL-13-producing CD8+ T cells are directly involved in modulating dermal fibrosis in SSc. The demonstration that CD8+ T cells homing to the skin early in the course of SSc are associated with accumulation of IL-13 is an important mechanistic contribution to the understanding of the pathogenesis of dermal fibrosis in SSc and may represent a potential target for therapeutic intervention., (Copyright © 2013 by the American College of Rheumatology.)

Objective: Epidemiology studies suggest that systemic sclerosis (SSc) is more common, occurs at a younger age, and is more severe in African Americans than Caucasians. However, the scleroderma autoantibody profile is very different between these 2 ethnic groups. This study was undertaken to examine the demographic and disease features, frequency and severity of internal organ system involvement, and survival in African American patients compared to Caucasian patients with SSc, giving particular attention to their serum autoantibody profiles., Methods: Demographic features, clinical characteristics, autoantibody profile, organ involvement, and survival were studied in consecutive African American and Caucasian patients with SSc whose visits were recorded between 1972 and 2007 as part of the Pittsburgh Scleroderma Database. The Medsger Severity Score for SSc was used to determine the severity of disease., Results: African American patients were more likely to have anti-topoisomerase I (anti-topo I), anti-U1 RNP, and anti-U3 RNP autoantibodies. In comparing African American and Caucasian patients with these antibodies, pulmonary fibrosis was found to be more frequent and more severe, and the rate of survival was decreased, in African American patients with anti-topo I antibodies compared to Caucasian patients with anti-topo I. Pulmonary fibrosis was also more severe in the anti-U1 RNP-positive patients, but this was not associated with a difference in survival between African Americans and Caucasians. Anti-U3 RNP was associated with more severe gastrointestinal involvement in African Americans compared to Caucasians., Conclusion: African Americans with SSc have more severe disease complications compared to Caucasians with SSc, and this is associated with both the type of autoantibody present and the severity of interstitial lung disease. Thus, it is hoped that early aggressive intervention in African Americans with interstitial lung disease will improve outcomes., (Copyright © 2012 by the American College of Rheumatology.)

Objective: Classification criteria for systemic sclerosis (SSc; scleroderma) are being updated. Our objective was to select a set of items potentially useful for the classification of SSc using consensus procedures, including the Delphi and nominal group techniques (NGT)., Methods: Items were identified through 2 independent consensus exercises performed by the Scleroderma Clinical Trials Consortium and the European League Against Rheumatism Scleroderma Trials and Research Group. The first-round items from both exercises were collated and redundancies were removed, leaving 168 items. A 3-round Delphi exercise was performed using a 1-9 scale (where 1 = completely inappropriate and 9 = completely appropriate) and a consensus meeting using NGT was conducted. During the last Delphi round, the items were ranked on a 1-10 scale., Results: In round 1, 106 experts rated the 168 items. Those with a median score of <4 were removed, resulting in a list of 102 items. In round 2, the items were again rated for appropriateness and subjected to a consensus meeting using NGT by European and North American SSc experts (n = 16), resulting in 23 items. In round 3, SSc experts (n = 26) then individually scored each of the 23 items in a last Delphi round using an appropriateness score (1-9) and ranking their 10 most appropriate items for the classification of SSc. Presence of skin thickening, SSc-specific autoantibodies, abnormal nailfold capillary pattern, and Raynaud's phenomenon ranked highest in the final list that also included items indicating internal organ involvement., Conclusion: The Delphi exercise and NGT resulted in a set of 23 items for the classification of SSc that will be assessed for their discriminative properties in a prospective study., (Copyright © 2012 by the American College of Rheumatology.)

Objectives: To compare systemic sclerosis (SSc) patients with and without anti-PM-Scl antibody., Methods: We reviewed the medical records of 76 anti-PM-Scl antibody positive SSc patients and 2349 anti-PMScl negative SSc patients first evaluated during 1980-2004. Patients were included if they had a clinical diagnosis of SSc either alone or in overlap with another connective tissue disease. Anti-PM-Scl antibody was screened for by indirect immunofluorescence and tested by Ouchterlony double immunodiffusion., Results: Anti-PM-Scl antibody positive patients had a significantly higher frequency of a positive ANA with nucleolar staining (87% vs. 32%, p<0.0001) and were younger at both symptom onset (p=0.004) and first physician diagnosis of SSc (p<0.001). They were classified more often as having overlap with another connective tissue disease, particularly polymyositis-dermatomyositis, and more frequently had limited cutaneous involvement (72% vs. 52%, p=0.001). Maximal skin thickening was less in anti-PM-Scl antibody patients (mean modified Rodnan total skin score 6.0±6.3 vs. 15.9±14.2, p<0.001). Anti-PM-Scl antibody positive patients less frequently had peripheral vascular (91% vs. 98%, p=0.0002) and gastrointestinal (52% vs. 79%, p=0.0001) disease. Lung involvement overall had a similar distribution between both groups. However, radiographic evidence of pulmonary fibrosis was more frequent in anti-PM-Scl antibody positive patients (50% vs. 37%, p=0.05) and pulmonary arterial hypertension was less often detected (5% vs. 15%, p<0.04). Skeletal muscle involvement (51% vs. 14%, p<0.0001) and subcutaneous calcinosis (p<0.003) were both significantly more often observed in anti-PM-Scl antibody positive patients. Joint, heart, and kidney involvement were similar in both groups. Overall survival was significantly better for anti-PM-Scl antibody positive patients (10 year cumulative survival rate 91% vs. 65%, p=0.0002). After adjustment for age, sex and limited vs. diffuse cutaneous involvement, patients with anti-PM-Scl antibody were significantly less likely to die (HR=0.32, 95% CI, [0.14, 0.72] p=0.006)., Conclusions: SSc patients with anti-PM-Scl antibody are younger and significantly more often have limited cutaneous involvement, skeletal muscle disease, pulmonary fibrosis and calcinosis compared to anti-PM-Scl antibody negative SSc patients. Ten-year cumulative survival is significantly better in anti-PM-Scl antibody positive SSc patients.

Objective: Classification criteria for systemic sclerosis (SSc; scleroderma) are being updated jointly by the American College of Rheumatology and European League Against Rheumatism. Potential items for classification were reduced to 23 using Delphi and nominal group techniques. We evaluated the face, discriminant, and construct validity of the items to be further studied as potential criteria., Methods: Face validity was evaluated using the frequency of items in patients sampled from the Canadian Scleroderma Research Group, 1000 Faces of Lupus, and the Pittsburgh, Toronto, Madrid, and Berlin connective tissue disease (CTD) databases. Patients with SSc (n = 783) were compared to 1,071 patients with diseases similar to SSc (mimickers): systemic lupus erythematosus (n = 499), myositis (n = 171), Sjögren's syndrome (n = 95), Raynaud's phenomenon (RP; n = 228), mixed CTD (n = 29), and idiopathic pulmonary arterial hypertension (PAH; n = 49). Discriminant validity was evaluated using odds ratios (ORs). For construct validity, empirical ranking was compared to expert ranking., Results: Compared to mimickers, patients with SSc were more likely to have skin thickening (OR 427); telangiectasias (OR 91); anti-RNA polymerase III antibody (OR 75); puffy fingers (OR 35); finger flexion contractures (OR 29); tendon/bursal friction rubs (OR 27); anti-topoisomerase I antibody (OR 25); RP (OR 24); fingertip ulcers/pitting scars (OR 19); anticentromere antibody (OR 14); abnormal nailfold capillaries (OR 10); gastroesophageal reflux disease symptoms (OR 8); antinuclear antibody, calcinosis, dysphagia, and esophageal dilation (all OR 6); interstitial lung disease/pulmonary fibrosis (OR 5); and anti-PM-Scl antibody (OR 2). Reduced carbon monoxide diffusing capacity, PAH, and reduced forced vital capacity had ORs of <2. Renal crisis and digital pulp loss/acroosteolysis did not occur in SSc mimickers (OR not estimated). Empirical and expert ranking were correlated (Spearman's ρ = 0.53, P = 0.01)., Conclusion: The candidate items have good face, discriminant, and construct validity. Further item reduction will be evaluated in prospective SSc and mimicker cases., (Copyright © 2012 by the American College of Rheumatology.)